Summary GnRH-1 neurons are essential for sexual competence and fertility in vertebrates. During development, GnRH-1 neurons migrate from the embryonic nasal area into the brain, where they eventually localize to the hypothalamus to control the release of gonadotropins from the pituitary gland. Defects in GnRH-1 migration cause various forms of hypogonadotropic hypogonadism (HH) in humans, which is characterized by delayed pubertal onset, hypogonadism and infertility. HH in humans manifests clinically as either Kallmann syndrome (KS) or normosmic idiopathic HH (nIHH). In KS, HH is associated with deficiencies in the sense of smell. This association led to the long-held, prevailing view that the GnRH-1 neurons migrate from the nose to the hypothalamus along the axons of olfactory and vomeronasal sensory neurons. However, our recent data suggest that the migration of the GnRH-1 neurons to the hypothalamus may rely on the terminal nerve (TN), which is formed by neurons distinct from the olfactory and vomeronasal sensory neurons. KS and nIHH are often associated with several non-reproductive anomalies including craniofacial defects, cleft/lip palate and dental agenesis. Craniofacial mesenchymal tissues play a pivotal role in controlling neuronal development and differentiation in the nasal area. Dysregulations in Sonic Hedgehog signaling can cause various craniofacial abnormalities, including holoprosencephaly, midline defects, cleft lip/palate and dental agenesis. Expression of genes downstream of hedgehog critically depend on interactions with the glioblastoma gene products (Gli) family of transcription factors (Gli1, Gli2, and Gli3). By analyzing whole exome sequencing data from a cohort of 580 patients affected by HH and KS, we identified candidate rare Gli3 point mutations. Our central hypothesis is that loss of Gli3 alters the expression of inductive signals, released by nasal mesenchyme and brain, which are necessary for terminal nerve and GnRH-1 neuronal development. We propose that this mechanism underlies KS and nIHH in humans. By exploiting mouse genetics, cutting edge imaging, human whole genome sequencing, organotypic cultures and site direct mutagenesis experiments, we will discover new mechanisms by which inductive factors modulate the hedgehog-Gli signaling system to control formation of a functional GnRH-1 system in vertebrates. Successful completion of our study will generate crucial clinical information for diagnostics and designing novel therapeutic approaches for KS and nIHH in humans.